ABSTRACT Huntington?s disease (HD) is a devastating neurological disease to which no pharmacological interventions are yet available to cure the disease. HD is caused by a mutation in the huntingtin gene consisting of an expanded CAG repeat. We recently demonstrated a regulatory role of APE1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, on mitochondrial (mt) function. First, silencing APE1 caused reductions of mt respiratory capacity in mutant huntingtin (mhtt)-expressing mouse and human cells. Second, levels of APE1 in the mt decreased in mutant HD cells following an oxidative insult, suggesting that mutant htt may interfere with the mt import of APE1. These observations suggest a novel mechanism for APE1 on the maintenance of mt function in HD. APE1 not only exhibits DNA repair activity of endogenous and exogenous oxidative and alkylating damage via BER, but also functions as a reduction-oxidation (redox) co-activator of certain transcription factors involved in neuronal survival. Whether APE1 DNA repair function, its redox activity or both are essential for maintenance of mt function and APE1 mt localization in HD is not known. Thus, our main objective is to determine the mechanisms of APE1- mediated mt dysfunction in the context of mutant htt. This proposal will test the overall hypothesis that mhtt mediates mt dysfunction and neurodegeneration by targeting APE1. To test our hypothesis, we will determine what mechanism(s) might trigger APE1-associated mt dysfunction in the context of the htt mutation by determining if 1) Mutant htt affects the repair of mtDNA and mitochondrial function by preventing APE1 activity and localization into the mitochondria and 2) APE1 DNA repair or redox activity (or both) are essential for the maintenance of mt function. This study is likely to provide insight into a possible regulatory mechanism of Ape1 in mhtt-induced mt dysfunction and neurodegeneration.